Human papillomaviruses (HPVs) are one the most common sexually transmitted diseases. These small DNA tumor viruses also are the causal agents for virtually all cervical cancers, other anogenital cancers, and a subset of oral cancers. The same subset of 'high risk'HPVs contribute to all of these cancers, with HPV16 being the virus genotype most commonly associated with each cancer. In this project we will determine whether the inhibition of expression of viral genes implicated in an early step of viral infection, the establishment of the viral genome as a nuclear plasmid, can lead to a reduced rate of infection. For these proof of principle studies, we will establish assays for monitoring the effect of siRNAs designed to knockdown expression of relevant papillomaviral genes, optimize the delivery of siRNAs to mucosal epithelia of the female reproductive tract and monitor the efficacy of papillomaviral-specific siRNAs in inhibiting genital infections by Rhesus papillomavirus (RhPV) in its cognate host. RhPV represents the closest animal model virus for studying the infection by anogenital HPVs. From these studies we will learn whether interference with the establishment of the papillomavirus DNA as a replicon in infected cells can reduce the onset of disease.